title: A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.
abstract: The ability of activation-induced cytidine deaminase (AID) to efficiently mediate class-switch recombination (CSR) is dependent on its phosphorylation at Ser38; however, the trigger that induces AID phosphorylation and the mechanism by which phosphorylated AID drives CSR have not been elucidated. Here we found that phosphorylation of AID at Ser38 was induced by DNA breaks. Conversely, in the absence of AID phosphorylation, DNA breaks were not efficiently generated at switch (S) regions in the immunoglobulin heavy-chain locus (Igh), consistent with a failure of AID to interact with the endonuclease APE1. Additionally, deficiency in the DNA-damage sensor ATM impaired the phosphorylation of AID at Ser38 and the interaction of AID with APE1. Our results identify a positive feedback loop for the amplification of DNA breaks at S regions through the phosphorylation- and ATM-dependent interaction of AID with APE1.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.
authors.forename: Bao Q
authors.initials: BQ
authors.lastname: Vuong
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.
authors.forename: Kayleigh
authors.initials: K
authors.lastname: Herrick-Reynolds
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.|Immunology and Microbial Pathogenesis Program, Weill-Cornell Graduate School of Medical Sciences, New York, New York, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Vaidyanathan
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Pucella
authors.affiliation: Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Ucher
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Donghia
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Gu
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Nicolas
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.|Immunology and Microbial Pathogenesis Program, Weill-Cornell Graduate School of Medical Sciences, New York, New York, USA.
authors.forename: Urszula
authors.initials: U
authors.lastname: Nowak
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.
authors.forename: Numa
authors.initials: N
authors.lastname: Rahman
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Strout
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mills
authors.affiliation: Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Stavnezer
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, New York, USA.|Immunology and Microbial Pathogenesis Program, Weill-Cornell Graduate School of Medical Sciences, New York, New York, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D053903:DNA Breaks, Double-Stranded; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000276:immunology*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D012694:Serine / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007143:Immunoglobulin Heavy Chains; D012694:Serine; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D003564:Cytidine Deaminase; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase